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Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs.

Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, Agrawal A - PLoS ONE (2015)

Bottom Line: Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect.Exhaled NO was reduced in both these groups.This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India.

ABSTRACT
Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.

No MeSH data available.


Related in: MedlinePlus

Arginine-NO pathway.
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pone.0129850.g007: Arginine-NO pathway.

Mentions: The principal finding is that the metabolic syndrome in non-obese HFR mice was associated with increased baseline lung resistance, airway hyperresponsiveness, and decreased exhaled NO. This was similar to observed changes in obese HFA mice except that during methacholine challenge, the increase in lung resistance was greater in obese (HFA) mice than those with only metabolic syndrome (HFR). Also, a large increase in elastance was seen exclusively in the HFA group. This is suggestive of derecruitment of peripheral lung units and it is likely that the constant 2 cm H2O PEEP during ventilation was sufficient to prevent peripheral airway closure in normal weight mice (HFR and control) but not obese mice (HFA). In support, while there was a possible increase in collagen content in lungs of both HFA and HFR mice, there was no significant parenchymal abnormality in either group. Irrespective of these differences between HFA and HFR mice, the increased resistance to airflow, with low levels of exhaled NO and lack of inflammatory cell infiltrate, is very similar to the “obese-asthma” phenotype in humans [30]. It is likely that this obese-asthmatic phenotype could be driven by abnormal Arginine-NO metabolism, as suggested by Holguin et al and us [12,33,31]. We have previously suggested that ADMA is a common link between asthma and metabolic syndrome [12]. While ADMA can bind to NOS in place of L-arginine, the methyl group prevents transfer of electrons to the nitrogen, preventing formation of NO and leading to formation of superoxide anion. NO generated from iNOS, which is relatively resistant to ADMA, can react with superoxide to form peroxynitrite, which can lead to protein nitrosylation and organelle damage. In obese HFA mice, there was additionally an increase in arginse expression and reduced levels of L-arginine, which by virtue of lowering arginine bioavailability could explain the greater AHR in such mice. Similar increase in ADMA and oxo-nitrative stress has previously been reported in allergic asthma [33,43,40] and we speculate that this could be a major mechanism, unrelated to any classical immune response, which may be responsible for the obese-asthma phenotype such that airway stress and hyperresponsiveness develop without any cellular inflammation. We have previously shown that such mice have evidence of mitochondrial derangement and Fig 7 shows a schematic of how the current findings may explain that observation [44, 45].


Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma-Like Changes in Lungs.

Singh VP, Aggarwal R, Singh S, Banik A, Ahmad T, Patnaik BR, Nappanveettil G, Singh KP, Aggarwal ML, Ghosh B, Agrawal A - PLoS ONE (2015)

Arginine-NO pathway.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476757&req=5

pone.0129850.g007: Arginine-NO pathway.
Mentions: The principal finding is that the metabolic syndrome in non-obese HFR mice was associated with increased baseline lung resistance, airway hyperresponsiveness, and decreased exhaled NO. This was similar to observed changes in obese HFA mice except that during methacholine challenge, the increase in lung resistance was greater in obese (HFA) mice than those with only metabolic syndrome (HFR). Also, a large increase in elastance was seen exclusively in the HFA group. This is suggestive of derecruitment of peripheral lung units and it is likely that the constant 2 cm H2O PEEP during ventilation was sufficient to prevent peripheral airway closure in normal weight mice (HFR and control) but not obese mice (HFA). In support, while there was a possible increase in collagen content in lungs of both HFA and HFR mice, there was no significant parenchymal abnormality in either group. Irrespective of these differences between HFA and HFR mice, the increased resistance to airflow, with low levels of exhaled NO and lack of inflammatory cell infiltrate, is very similar to the “obese-asthma” phenotype in humans [30]. It is likely that this obese-asthmatic phenotype could be driven by abnormal Arginine-NO metabolism, as suggested by Holguin et al and us [12,33,31]. We have previously suggested that ADMA is a common link between asthma and metabolic syndrome [12]. While ADMA can bind to NOS in place of L-arginine, the methyl group prevents transfer of electrons to the nitrogen, preventing formation of NO and leading to formation of superoxide anion. NO generated from iNOS, which is relatively resistant to ADMA, can react with superoxide to form peroxynitrite, which can lead to protein nitrosylation and organelle damage. In obese HFA mice, there was additionally an increase in arginse expression and reduced levels of L-arginine, which by virtue of lowering arginine bioavailability could explain the greater AHR in such mice. Similar increase in ADMA and oxo-nitrative stress has previously been reported in allergic asthma [33,43,40] and we speculate that this could be a major mechanism, unrelated to any classical immune response, which may be responsible for the obese-asthma phenotype such that airway stress and hyperresponsiveness develop without any cellular inflammation. We have previously shown that such mice have evidence of mitochondrial derangement and Fig 7 shows a schematic of how the current findings may explain that observation [44, 45].

Bottom Line: Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect.Exhaled NO was reduced in both these groups.This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Translational Research in Asthma and Lung Disease, CSIR- Institute of Genomics and Integrative Biology, Delhi, India.

ABSTRACT
Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high-sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high-fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high-fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis.

No MeSH data available.


Related in: MedlinePlus